- Discovery of selective fragment-sized immunoproteasome inhibitors
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Proteasomes contribute to maintaining protein homeostasis and their inhibition is beneficial in certain types of cancer and in autoimmune diseases. However, the inhibition of the proteasomes in healthy cells leads to unwanted side-effects and significant effort has been made to identify inhibitors specific for the immunoproteasome, especially to treat diseases which manifest increased levels and activity of this proteasome isoform. Here, we report our efforts to discover fragment-sized inhibitors of the human immunoproteasome. The screening of an in-house library of structurally diverse fragments resulted in the identification of benzo[d]oxazole-2(3H)-thiones, benzo[d]thiazole-2(3H)-thiones, benzo[d]imidazole-2(3H)-thiones, and 1-methylbenzo[d]imidazole-2(3H)-thiones (with a general term benzoXazole-2(3H)-thiones) as inhibitors of the chymotrypsin-like (β5i) subunit of the immunoproteasome. A subsequent structure-activity relationship study provided us with an insight regarding growing vectors. Binding to the β5i subunit was shown and selectivity against the β5 subunit of the constitutive proteasome was determined. Thorough characterization of these compounds suggested that they inhibit the immunoproteasome by forming a disulfide bond with the Cys48 available specifically in the β5i active site. To obtain fragments with biologically more tractable covalent interactions, we performed a warhead scan, which yielded benzoXazole-2-carbonitriles as promising starting points for the development of selective immunoproteasome inhibitors with non-peptidic scaffolds.
- Kollár, Levente,Gobec, Martina,Szilágyi, Bence,Proj, Matic,Knez, Damijan,ábrányi-Balogh, Péter,Petri, László,Imre, Tímea,Bajusz, Dávid,Ferenczy, Gy?rgy G.,Gobec, Stanislav,Keser?, Gy?rgy M.,Sosi?, Izidor
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- C2-Selective Branched Alkylation of Benzimidazoles by Rhodium(I)-Catalyzed C-H Activation
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Herein, we report a Rh(I)/bisphosphine/K3PO4 catalytic system allowing for the first time the selective branched C-H alkylation of benzimidazoles with Michael acceptors. Branched alkylation with N,N-dimethyl acrylamide was successfully applied to the alkylation of a broad range of benzimidazoles incorporating a variety of N-substituents and with both electron-rich and -poor functionality displayed at different sites of the arene. Moreover, the introduction of a quaternary carbon was achieved by alkylation with ethyl methacrylate. The method was also shown to be applicable to the C2-selective branched alkylation of azabenzimidazoles.
- Tran, Ga?l,Confair, Danielle,Hesp, Kevin D.,Mascitti, Vincent,Ellman, Jonathan A.
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p. 9243 - 9252
(2017/09/11)
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- Discovery of 2-iminobenzimidazoles as potent hepatitis C virus inhibitors with a novel mechanism of action
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In this report we describe 2-iminobenzimidazole (IBI) analogs, identified during the course of a phenotypic high-throughput screening campaign, as novel hepatitis C virus (HCV) inhibitors. A series of IBI derivatives was synthesized and evaluated for their inhibitory activity against infectious HCV. Among the IBIs derivatives studied in this work, we identified promising compounds with high antiviral efficacy, high selectivity index and good microsomal stability. Noteworthy, the IBI series exhibited inhibitory activity on early and late steps of the viral cycle, but not in the HCV replicon system demonstrating a mechanism of action distinct from clinical-stage and approved anti-HCV drugs. Overall, our results suggest that IBIs are predestinated for further exploration as lead compounds for novel HCV interventions.
- Windisch, Marc Peter,Jo, Suyeon,Kim, Hee-Young,Kim, Soo-Hyun,Kim, Keumhyun,Kong, Sunju,Jeong, Hyangsuk,Ahn, Sujin,No, Zaesung,Hwang, Jong Yeon
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- Discovery of a 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione series of inhibitors of HIV-1 capsid assembly
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The discovery of a 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione series of inhibitors of HIV-1 capsid assembly is described. Synthesis of analogs of the 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione hit established structure-activity relationships. Replacement of the enamine functionality of the hit series with either an imidazole or a pyrazole ring led to compounds that inhibited both capsid assembly and reverse transcriptase. Optimization of the bicyclic benzodiazepine scaffold to include a 3-phenyl substituent led to lead compound 48, a pure capsid assembly inhibitor with improved antiviral activity.
- Fader, Lee D.,Bethell, Richard,Bonneau, Pierre,B?s, Michael,Bousquet, Yves,Cordingley, Michael G.,Coulombe, René,Deroy, Patrick,Faucher, Anne-Marie,Gagnon, Alexandre,Goudreau, Nathalie,Grand-Ma?tre, Chantal,Guse, Ingrid,Hucke, Oliver,Kawai, Stephen H.,Lacoste, Jean-Eric,Landry, Serge,Lemke, Christopher T.,Malenfant, Eric,Mason, Stephen,Morin, Sébastien,O'Meara, Jeff,Simoneau, Bruno,Titolo, Steve,Yoakim, Christiane
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scheme or table
p. 398 - 404
(2011/03/17)
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- Bicyclic Benzimidazole Compounds and Their Use as Metabotropic Glutamate Receptor Potentiators
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Compounds of Formula I: wherein A, B, D, L, R1, R2, R3, R4, m, and n are as defined for Formula I in the description. The invention also relates to processes for the preparation of the compounds and to new intermediates employed in the preparation, pharmaceutical compositions containing the compounds, and to the use of the compounds in therapy.
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Page/Page column 56
(2009/08/14)
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- MONOCYCLIC AND BICYCLIC COMPOUNDS AND METHODS OF USE
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Compounds are provided that act as potent antagonists of the CCR1 receptor, and have in vivo anti-inflammatory activity. The compounds are generally monocyclic and bicyclic compounds and are useful in pharmaceutical compositions, methods for the treatment of CCR1-mediated diseases, and as controls in assays for the identification of competitive CCR1 antagonists.
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Page/Page column 85
(2010/11/26)
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- Synthesis and antiparasitic activity of 2-(Trifluoromethyl)benzimidazole derivatives
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2-(Trifluoromethyl)benzimidazole derivatives substituted at the 1-, 5-, and 6-positions have been synthesized and in vitro tested against the protozoa Giardia lamblia, Entamoeba histolytica, and the helminth Trichinella spiralis. Results indicate that all the compounds tested are more active as antiprotozoal agents than Albendazole and Metronidazole. One compound (20) was as active as Albendazole against T. spiralis. These compounds were also tested for their effect on tubulin polymerization and none inhibited tubulin polymerization.
- Navarrete-Vazquez, Gabriel,Cedillo, Roberto,Hernandez-Campos, Alicia,Yepez, Lilian,Hernandez-Luis, Francisco,Valdez, Juan,Morales, Raul,Cortes, Rafael,Hernandez, Manuel,Castillo, Rafael
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p. 187 - 190
(2007/10/03)
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- Linear free energy substitutent effect on flavin redox chemistry
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A systematic study on the effect of various substituents at the 7- and/or 8-position on the redox properties of isoalloxazines (flavins) is reported. The redox properties of these flavin derivatives were studied by cyclic voltammetry in 100 mM, pH 7.4 HEPES and 200 mM, pH 10 borate buffers. The magnitude and direction of the effect was dependent on the nature and location of the substituent. The redox potentials of the substituted flavins were correlated with the Hammett σ value of the substituents.
- Hasford, Justin J.,Rizzo, Carmelo J.
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p. 2251 - 2255
(2007/10/03)
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